The N-methyl-D-aspartate (NMDA) subtype of glutamate receptor and its associated cation channel are allosterically coupled to a strychnine-insensitive glycine receptor, forming a "supramolecular complex" (1). Excessive activation of this "supramolecular complex" has been linked to various neuropsychopharmacological disorders including seizure disorders, ischemic brain damage, and other neuropathologies. Both structural requirements for ligand binding to strychnine-insensitive glycine receptors on this "supramolecular complex" and their regional distribution in the central nervous system have been reported to differ remarkably from strychnine-sensitive glycine receptors. It has also been reported that there is an absolute requirement that there be present glycine for activation of NMDA receptor complexes as expressed in Xenopus oocytes (19).
Skolnick et al, in copending U.S. patent application Ser. No. 07/390,745, filed on Aug. 8, 1989, discloses a method of treating neuropharmacological disorders which result from excessive activation of the NMDA-receptor complex, by administering to a patient an effective neuropsychopharmacological disorder-treating amount of a compound possessing partial agonist properties for the strychnine-insensitive glycine modulatory site of the NMDA-receptor complex. Suitable partial agonists of the NMDA-receptor complex, disclosed by Skolnick et al, include 1-aminocyclopropanecarboxylic acid, and derivatives thereof. Copending U.S. patent application Ser. No. 07/390,745, filed on Aug. 8, 1989, is incorporated herein by reference.
1-Aminocyclopropane-carboxylic acid (ACPC) has been shown to be a potent and selective partial agonist of the strychnine-insensitive glycine binding site of the NMDA-receptor complex (12). The compound 2-amino-7-phosphonoheptanoic acid has been reported to be a competitive antagonist at the NMDA receptor complex (Perkins, 981) reviewed in (1). The compound (+)-5-methyl-1? ,11-dihydro-5H-dibenzo[a,d]cycloheptene -5,10-imine has been reported to be a non-competitive NMDA antagonist thought to act within the NMDA-gated cation channel (11).